Increasing heart vascularisation after myocardial infarction using brain natriuretic peptide stimulation of endothelial and WT1+ epicardial cells
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Abstract
Brain natriuretic peptide (BNP) treatment increases heart function and decreases heart dilation after myocardial infarction (MI). Here, we investigated whether part of the cardioprotective effect of BNP in infarcted hearts related to improved neovascularisation. Infarcted mice were treated with saline or BNP for 10 days. BNP treatment increased vascularisation and the number of endothelial cells in all areas of infarcted hearts. Endothelial cell lineage tracing showed that BNP directly stimulated the proliferation of resident endothelial cells via NPR-A binding and p38 MAP kinase activation. BNP also stimulated the proliferation of WT1 + epicardium-derived cells but only in the hypoxic area of infarcted hearts. Our results demonstrated that these immature cells have a natural capacity to differentiate into endothelial cells in infarcted hearts. BNP treatment increased their proliferation but not their differentiation capacity. We identified new roles for BNP that hold potential for new therapeutic strategies to improve recovery and clinical outcome after MI.
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###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on August 16 2020, follows.
Summary
The manuscript entitled "Increasing heart vascularisation using brain natriuretic peptide stimulation of endothelial and WT1+ epicardial cells" by Li et al. reports data of myocardial angiogenesis in mice subjected to experimental myocardial infarction. The study indicates that repeated intraperitoneal injections of synthetic BNP or oral treatment with Entresto, a drug inhibiting neprilysin-mediated degradation of the endogenous natriuretic peptides, possibly improves cardiac vascularization after ischemia.
Microvascular dysfunction after acute myocardial infarction (MI) is a major clinical problem. Although primary percutaneous coronary intervention (PCI) has markedly improved patients' survival, …
###This manuscript is in revision at eLife
The decision letter after peer review, sent to the authors on August 16 2020, follows.
Summary
The manuscript entitled "Increasing heart vascularisation using brain natriuretic peptide stimulation of endothelial and WT1+ epicardial cells" by Li et al. reports data of myocardial angiogenesis in mice subjected to experimental myocardial infarction. The study indicates that repeated intraperitoneal injections of synthetic BNP or oral treatment with Entresto, a drug inhibiting neprilysin-mediated degradation of the endogenous natriuretic peptides, possibly improves cardiac vascularization after ischemia.
Microvascular dysfunction after acute myocardial infarction (MI) is a major clinical problem. Although primary percutaneous coronary intervention (PCI) has markedly improved patients' survival, despite epicardial reperfusion more than 30% of patients show signs of microvascular dysfunction leading to adverse left ventricular remodeling and heart failure. Impaired angiogenesis can contribute to myocardial tissue damage. Based on experimental studies, several clinical trials aimed to improve myocardial angiogenesis via intracoronary administration of vascular growth factors, gene transfer or bone marrow mononuclear cells, in patients who had successful primary PCI, but the results were disappointing. A better knowledge of the cellular pathways regulating myocardial (re)perfusion after ischemia is necessary to search for therapeutic strategies capable to restore the microvascular network and flow. The here presented study aimed to elucidate whether B-type natriuretic peptide (BNP) can improve myocardial postischemic angiogenesis in as well as the potential pharmacological, therapeutic implications. Hence, this experimental, „preclinical" study addresses an important, clinically relevant question.
Overall this study follows a very original question. But it includes many different data sets in somehow incomplete way, many of them generated with "NMC". It would benefit a lot by concentrating in a clean way on some concrete aspects. Mechanistic studies should be preferentially conducted with sorted or cultured endothelia instead of a mixed cell population (NMC, containing fibroblasts, pericytes, inflammatory cells, besides endothelial cells).
Essential Revisions
Certain parts of the study should be completed. For example, why don't the authors present a fine and extensive analysis of cardiac function in animals treated with BNP? In the same way, the authors should complement their experimental approaches with an analysis of all parameters of cardiac remodeling and in particular infarct size and interstitial fibrosis.
Conversely, the authors made the effort to analyze cardiac function in animals treated with LCZ696 (Figure 9). However, there is no statistical analysis of these data? or the differences are not significant? in this case, what is the interest of a treatment that increases capillary density without modifying cardiac function? It is however likely that an analysis of cardiac function beyond 10 days post-MI could give significantly different results.
The authors should analyze whether or not LCZ696 directly stimulates the proliferation of resident mature endothelial cells and/or that of WT1+ cells.
Results, page 5, para 1: the authors state that "first they determined whether ip BNP acted directly or indirectly on cardiac cells". But there is no single data set in this manuscript allowing to conclude that the observed effects are directly derived from endothelial actions of BNP. As they mention before, BNP acts on many types of cells and organs, and the observed effects could also be "indirect".
Results, page 5, para 3: plasma cGMP levels are a poor index of cardiac actions of BNP. It would be more meaningful to measure cardiac cGMP levels.
Results, page 5, para 4: it is strange to use the phosphorylation of phospholamban (PLB) as index of BNP activity. This manuscript focuses on angiogenesis. PLB is a regulatory protein in cardiomyocytes. Where is the link to endothelial regeneration?
Page 6, top: BNP increased phosphorylation of PLB by nearly 200-fold in "non-myocyte cells" from the heart. Which cells are these? Is this fraction contaminated by cardiomyocytes? Which non-myocytes have such high PLB levels?
How were BNP plasma levels in BNP versus vehicle treated mice after MI? Did Entresto increase BNP plasma levels and to what extend?
Most in vitro and ex vivo studies were performed with NMCs. How many endothelial cells are contained in such heterogenous populations?
Some basic parameters are missing: how did BNP administration affect cardiac contractile functions as well as the infarct area and area at risk? Did exogenous BNP lower arterial blood pressure?
Page 9: how does BNP, via NPR-A/cGMP-signaling, increase MAPK pp38? What is the signaling pathway and do the authors have any hint that this signaling pathway was also activated by BNP in vivo (in endothelial cells in situ)?
Page 11 presents a section entitled "Increased vascularization in infarcted hearts after LCZ696 treatment". But in the corresponding Figure 9, there is no single data set showing „statistically significant effects of entresto". The figure just shows some preliminary data and trends obtained with very few mice.
Figure 1C: it is surprising that the basal levels of pPLB were so low (-). Normally, after MI in mice the endogenous ventricular expression levels of ANP and BNP significantly raise. Was there a difference in pPLB between sham and MI mice (vehicle treatments)?
Figure 1D: which types of non-myocyte cells express such high pPLB levels and what is the functional meaning?
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